Chemical formula
of C16H13ClN2OMolecular
mass 284.7 g/mol first marketed as Valium by Hoffmann-La
Roche, is a benzodiazepine derivative drug. It possesses anxiolytic,
anticonvulsant, sedative, skeletal muscle relaxant and amnestic
properties. It is commonly used for treating anxiety, insomnia,
seizures, alcohol withdrawal, and muscle spasms. It may also be
used before certain medical procedures (such as endoscopies) to
reduce tension and anxiety, and in some surgical procedures to
induce amnesia.[1][2]

Diazepam is
a core medicine in the World Health Organization's "Essential
Drugs List", which is a list of minimum medical needs for a basic
health care system.[3]
Diazepam is used to treat a wide range of conditions and has been
one of the most frequently prescribed medications in the world
for the past 40 years. It was invented by Dr. Leo Sternbach.

History

Diazepam was
the second benzodiazepine to be invented by Sternbach of Hoffmann-La
Roche, and was approved for use in 1963. It is two and a half
times more potent than its predecessor, chlordiazepoxide, which
it quickly surpassed in terms of sales. After this initial success,
other pharmaceutical companies began to introduce other benzodiazepine
derivatives.[4]

The benzodiazepines
gained popularity among medical professionals as an improvement
upon barbiturates, which have a comparatively narrow therapeutic
index, and are far more sedating at therapeutic doses. The benzodiazepines
are also far less dangerous; death rarely results from diazepam
overdose, except in cases where it is consumed with large amounts
of other depressants (such as alcohol or other sedatives).[5]

Diazepam was
the top-selling pharmaceutical in the United States from 1969
to 1982, with peak sales in 1978 of 2.3 billion tablets.[4] Diazepam along with oxazepam, nitrazepam and temazepam
represent 82% of the benzodiazepine market in Australia.[6]
While psychiatrists continue to prescribe diazepam for the short-term
relief of anxiety, neurology has taken the lead in prescribing
diazepam for the palliative treatment of certain types of epilepsy
and spastic activity, e.g., forms of paresis. It is also the first
line of defense for a rare disorder called stiff-person syndrome.[7].
Diazepam is also found in nature. Several plants, such as
potato and wheat, contain trace amounts of naturally occurring
diazepam and other benzodiazepines.[8]

Physical properties

Diazepam occurs
as solid white or yellow crystals and has a melting point of 131.5
to 134.5 °C. It is odorless, and has a slightly bitter taste.
The British Pharmacopoeia lists diazepam as being very slightly
soluble in water, soluble in alcohol and freely soluble in chloroform.
The United States Pharmacopoeia lists diazepam as soluble 1 in
16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and
practically insoluble in water. The pH of diazepam is neutral
(i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets
and 3 years for IV/IM solution.[9]
Diazepam is structurally related to quinazolines and is a hapten.[10]

Pharmacology

Diazepam is a
"classical" benzodiazepine, other classical benzodiazepines include;
clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam
and clorazepate.[12] Diazepam and other benzodiazepines may influence
neurosteroid metabolism and progesterone levels which in turn may
adversely influence the functions of the brain and reproductive
system. The pharmacological actions of benzodiazepines at the GABAa
receptor are similar to those of neurosteroids. Neuroactive steroids
are positive allosteric modulators of the GABAa receptor, enhancing
GABA function. Many benzodiazepines (diazepam, medazepam, estazolam,
flunitrazepam and nitrazepam) potently inhibit the enzymes involved
in the metabolism of neurosteroids. Long-term administration of
benzodiazepines may influence the concentrations of endogenous neurosteroids,
and thereby would modulate the emotional state. Factors which affect
benzodiazepines ability to alter neurosteroid levels depend on the
molecular make up of the individual benzodiazepine molecule. Presence
of a substituent at N1 position of the diazepine ring and/or the
chloro or nitro group at position 7 of the benzene ring contribute
to potent inhibition of the isoenzymes, and in turn a bromo group
at position 7 (for bromazepam) and additional substituents (3-hydroxy
group for oxazepam and tetrahydroxazole ring for cloxazolam and
oxazolam) decrease the inhibitory potency of benzodiazepines on
neurosteroids.[13] Diazepam
binds with high affinity to glial cells.[14.

Mechanism
of action

Diazepam is
a benzodiazepine that binds to a specific subunit on the GABAA
receptor at a site that is distinct from the binding site of the
endogenous GABA molecule.[19][20]The GABAA receptor is an
inhibitory channel which, when activated, decreases neurologic
activity.

Due to the
role of diazepam as a positive allosteric modulator of GABA, when
it binds to benzodiazepine receptors it causes inhibitory effects.
This arises from the hyperpolarization of the post-synaptic membrane,
due to the control exerted over negative chloride ions by GABAA
receptors.[19][21]

Benzodiazepines
including diazepam however, do not have any affect on the levels
of GABA in the brain.[22]

Diazepam appears
to act on areas of the limbic system, thalamus and hypothalamus,
inducing anxiolytic effects. Its actions are due to the enhancement
of GABA activity.[1][19] Benzodiazepine drugs including
diazepam increase the inhibitory processes in the cerebral cortex.[23]

The anticonvulsant
properties of diazepam and other benzodiazepines may be in part
or entirely due to binding to voltage-dependent sodium channels
rather than benzodiazepine receptors. Sustained repetitive firing
seems to be limited by benzodiazepines effect of slowing recovery
of sodium channels from inactivation.[24]

The muscle
relaxant properties of diazepam are produced via inhibition of
polysynaptic pathways in the spinal cord.[25]

Pharmacokinetics

When diazepam
is administered orally, it is rapidly absorbed and has a fast
onset of action. The onset of action is 1-5 minutes for IV administration
and 15-30 minutes for IM administration. The duration of diazepam's
peak pharmacological effects is 15 minutes to 1 hour for both
routes of administration.[26].
Peak plasma levels are achieved 30 minutes to 2 hours after
oral administration. When diazepam is administered as an intramuscular
injection, absorption is slow, erratic and incomplete.[27][11]

Diazepam is
highly lipid-soluble, and is widely distributed throughout the
body after administration. It easily crosses both the blood-brain
barrier and the placenta, and is excreted into breast milk. After
absorption, diazepam is redistributed into muscle and adipose
tissue. Continual daily doses of diazepam will quickly build up
to a high concentration in the body (mainly in adipose tissue),
which will be far in excess of the actual dose for any given day.[9][11]. There is preferential storage
of diazepam in some organs including the heart. Absortion by any
administered route and the risk of accumulation is significantly
increased in the neonate and there is clinical justification to
recommend the withdrawal of diazepam during pregnancy and breast
feeding.[28]. Diazepam is
metabolised via oxidative pathways in the liver via the cytochrome
P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5
days, and has several pharmacologically active metabolites. The
main active metabolite of diazepam is desmethyldiazepam (also
known as nordazepam or nordiazepam). Diazepam's
other active metabolites include temazepam and oxazepam. These
metabolites are conjugated with glucuronide, and are excreted
primarily in the urine. Because of these active metabolites, the
serum values of diazepam alone are not useful in predicting the
effects of the drug.[27][11][29]

Indications

Diazepam is
mainly used to treat anxiety, insomnia, and symptoms of acute
alcohol or opiate withdrawal. It is also used as a premedication
for inducing sedation, anxiolysis or amnesia prior to certain
medical procedures (e.g. endoscopy).[27]. Diazepam is rarely used for the
long-term treatment of epilepsy. This is due to the fact that
tolerance to the anticonvulsant effects of diazepam usually develops
within 6 to 12 months of treatment, effectively rendering it useless
for this purpose and also due to side effects - in particular
sedation.[9][31]. Diazepam has a broad spectrum of indications
(most of which are off-label), including: treatment of anxiety,
panic attacks, and states of agitation[27] ; treatment of status epilepticus,
adjunctive treatment of other forms of epilepsy[27] ; treatment of the symptoms of alcohol and opiate
withdrawal[27] ; short-term treatment of insomnia[27] ; treatment of tetanus, together with other measures
of intensive-treatment[32]
; initial management of mania, together with firstline drugs like
lithium, valproate or other antipsychotics; adjunctive treatment of painful muscle
conditions[7] ; adjunctive treatment of spastic muscular
paresis (para-/tetraplegia) caused by cerebral or spinal cord
conditions such as stroke, multiple sclerosis, spinal cord injury
(long-term treatment is coupled with other rehabilitative measures)[7]
; palliative treatment of stiff person syndrome[21]
; used to alleviate the symptoms of Lesch-Nyhan Syndrome ; pre-/postoperative
sedation, anxiolysis and/or amnesia (e.g. before endoscopic or
surgical procedures)[7]
;treatment of overdosage with hallucinogens or CNS stimulants[9] ; adjunctive treatment of drug-induced
seizures, resulting from exposure to sarin, VX, soman (or other
organophosphate poisons; See CANA), lindane, chloroquine, physostigmine,
or pyrethroids[9] ; emergency treatment of eclampsia,
along with IV magnesium sulfate ; prophylactic treatment of oxygen
toxicity during hyperbaric oxygen therapy.[33]
used in the treatment for irritable bowel syndrome.[34] ; and used to treat pain resulting from muscle spasms
caused by various spastic dystonias, including blepharospasm,
spasmodic dysphonia and Meige's Syndrome.

Side effects

Diazepam has
a range of side effects which are common to most benzodiazepines.
Most common side effects include: somnolence ; suppression of
REM sleep; addiction ; impaired motor function ; impaired coordination;
impaired balance; dizziness and nausea ; depression ; impaired
learning; anterograde amnesia (especially pronounced in higher
doses) ; cognitive deficits[40] ; reflex tachycardia[26] ; rare paradoxical side effects
can include: nervousness, irritability, insomnia, muscle cramps,
and in extreme cases, rage, and violence.[41][42][43] If these side effects are present,
diazepam treatment should be immediately terminated.

Benzodiazepines
such as diazepam impair learning and memory via their action on
benzodiazepine receptors which causes a dysfunction in the cholinergic
neuronal system.[44]

Diazepam may
impair the ability to drive vehicles or operate machinery. The
impairment is worsened by consumption of alcohol, because both
act as central nervous system depressants.[21].
During the course of therapy, tolerance to the sedative
effects usually develops, but not to the anxiolytic and myorelaxant
effects.[45]. Patients with severe attacks of
apnea during sleep may suffer respiratory depression (hypoventilation)
leading to respiratory arrest and death. Organic changes such
as leukopenia[46] and liver-damage of the cholostatic type with
or without jaundice (icterus) have been observed in a few cases.Diazepam in doses of 5 mg or more causes significant deterioration
in vigilance performance combined with increased feelings of sleepiness.[47]

References

Diazepam. PubChem. National Institute
of Health: National Library of Medicine (2006).

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